Phenylaminoethanol derivatives for treating hypertension

ABSTRACT

Compounds of the formula: ##STR1## and physiologically acceptable acid addition salts thereof, in which R 1  is 
     A. an arylalkyl group, the alkyl portion of which contains from 1 to 6 carbon atoms and the aryl portion of which may be substituted by one or more alkoxy groups or hydroxy groups; or 
     B. an aryloxyalkyl group, the alkyl portion of which contains from 1 to 6 carbon atoms, and the aryloxy portion of which is substituted with one or more alkoxy or hydroxy groups. 
     These compounds have a blacking action on both α- and β-adrenergic receptors and are useful in treating hypertension. Processes for the production of these compounds and pharmaceutical compositions containing them are also provided.

This is a division of application Ser. No. 420,547, filed Nov. 30, 1973,now U.S. Pat. No. 4,012,444, which is in turn a continuation ofapplication Ser. No. 50,979, filed June 29, 1970, and now abandoned.

This invention relates to novel-1-phenyl-2-aminoethanol derivativeshaving biological activity, and to compositions containing the same, andto processes for preparing such derivatives. It is an improvement of theinvention described in application Ser. No. 669,263, of Lunts et alfiled Sept. 20th, 1967.

In that application there are disclosed compounds of the formula:##STR2## and physiologically acceptable acid addition salts thereof inwhich: R₁ represents a hydrogen atom or a straight or branched chainalkyl radical containing from 1 to 6 carbon atoms;

R₂ represents a hydrogen atom or a benzyl group;

R₃ represents a hydrogen atom, or a straight or branched chain alkylradical containing from 1 to 6 carbon atoms, which radical may besubstituted by hydroxyl groups, amino groups or heterocyclic rings,containing one or more heteroatoms, for example morpholino, orrepresents a cycloalkyl, aralkyl or aryloxyalkyl radical, which radicalsmay optionally be substituted, for example by one or more alkoxy orhydroxy groups; and

X represents a hydroxyalkyl or hydroxyaralkyl radical having a straightor branched alkyl chain containing from 1 to 6 carbon atoms, or acarboxyl radical, or an alkoxy carbonyl radical of the formula --COOR₄,(where R₄ represents a straight or branched chain alkyl radicalcontaining from 1 to 6 carbon atoms), or represents a radical of theformula --CONHOH or --CONHNH₂ or an amido radical of the formula --CONR₅R₆ (where R₅ and R₆, which may be the same or different, each representsa hydrogen atom or an arylalkyl radical or a straight or branched chainalkyl radical containing from 1 to 6 carbon atoms which may besubstituted by hydroxyl or amino groups or where R₅ and R₆ together withthe adjacent nitrogen atom form a heterocyclic ring which may containfurther heteroatoms).

These compounds possess either stimulant or blocking actions onβ-adrenergic receptors.

This invention relates to certain novel-1-phenyl-2-aminoethanols whichfall within the general formula I given above but which have been foundto have the special and particular utility of blocking both the α- andβ-adrenergic receptors. They may be used as hypotensive agents and inthe treatment of peripheral disorders, such as Raynaud's disease, with aminimum of side effects. They are also of value in the treatment ofangina pectoris.

The invention therefore provides as new compounds, compounds of theformula: ##STR3## and physiologically acceptable acid addition saltsthereof, in which R¹ is

a. an arylalkyl group, the alkyl portion of which contains from 1 to 6carbon atoms and the aryl portion of which may be substituted by one ormore alkoxy groups or hydroxy groups

b. an aryloxyalkyl group, the alkyl portion of which contains from 1 to6 carbon atoms, and the aryloxy portion of which is substituted with oneor more alkoxy or hydroxy groups.

Preferred compounds according to the invention are those in which thealkyl portion of the group (a) or group (b) contains from 3 to 4 carbonatoms; in which, where the aryl portion or aryloxy portion contains analkoxy substituent, this contains from 1 to 6 carbon atoms, preferably 1to 4 carbon atoms, and is in particular a methoxy or ethoxy group.

A preferred aryl group is the phenyl group. A preferred aryloxy group isthe phenoxy group. More than one aryl or aryloxyl group may be attachedto the alkyl group and the definition aralkyl and aryloxyalkyl extendsto such possibilities. An example of such a case is1-methyl-3,3-diphenylpropyl.

Preferred compounds according to the invention are:

5-[1-hydroxy-2-(1-methyl-3-phenylpropyl)aminoethyl]salicylamide.

5-[1-hydroxy-2-(p-methoxy-α-methylphenethyl)aminoethyl]salicylamide.

5-[1-hydroxy-2-(2-p-methoxyphenoxy-1-methyl-ethyl)aminoethyl]salicylamide.

5-[1-hydroxy-2-(3-p-methoxyphenyl-1-methyl-propyl)aminoethyl]salicylamide.

5-[1-hydroxy-2-(3-phenylpropyl)aminoethyl]salicylamide hydrochloride.

5-[1-hydroxy-2-(2-o-methoxyphenoxy-1-methyl-ethyl)aminoethyl]salicylamide.

5-[1-hydroxy-2-(3-p-hydroxyphenyl-1-methylpropyl)aminoethyl]salicylamidehydrochloride.

5-[1-hydroxy-2-(1-methyl-4-phenylbutyl)aminoethyl]salicylamide.

5-[1-hydroxy-2-(1-methyl-3,3-diphenylpropyl)aminoethyl]salicylamide.

5-[2-(1,1-dimethyl-3-phenylpropyl)-amino-1-hydroxyethyl]salicylamide.

5-[1-hydroxy-2-(1-methyl-3-p-tolyl-propyl)aminoethyl]salicylamidehydrochloride.

5-{1-hydroxy-2-[3-(3,4-dimethoxypropyl)-1-methylpropyl]aminoethyl}salicylamidehydrochloride.

The invention extends to the physiologically acceptable acid additionsalts of the compounds of formula II, and these are in general preferredfor administration. Preferred salts include the hydrochloride, sulphate,maleate, tartrate and citrate.

The compounds according to the invention may exist in isomeric form byvirtue of the fact that they contain at least one asymmetric carbonatom. The invention includes all possible optically active forms andracemic mixtures of the compounds. The racemic mixtures may be resolvedby conventional methods, for example by salt formation with anoptionally active acid, followed by fractional crystallization. Thecompounds which include an asymmetric centre in the group R¹ have twocentres of asymmetry and can exist as four optical enantiomorphs. Anexample of the separation of a racemic mixture of such a compound intotwo racemic diastereoisomeric modifications is given hereinafter.

The 1-phenyl-2-aminoethanol derivatives of the invention may be preparedby a number of processes.

In one process, the compounds of the invention are prepared by reactingthe ketones of general formula III with a halogen, preferably bromine,to form the haloketones of formula IV, followed by condensation with anamine NHR² R³, in which R² represents hydrogen, benzyl or the group R¹,and R³ represents hydrogen or benzyl, to give the aminoketones offormula V. ##STR4## X represents the group --CONH₂, or a groupconvertible thereto.

The carbonyl group is then reduced to a CHOH group with a suitablereducing agent, for example a complex metal hydride such as sodiumborohydride, or by catalytic hydrogenation, to give the1-phenyl-2-aminoethanol derivatives of formula VI. ##STR5##

The compounds of the formula VI in which X is a --CONH₂ group, R²represents the radical R¹, and R³ is a hydrogen atom are compounds ofthe invention. Other compounds of formula VI may be converted tocompounds of the invention by the following procedures.

The group X is conveniently an alkoxycarbonyl radical of formula--COOR⁴, where R⁴ is a straight or branched chain alkyl radicalcontaining from 1 to 6 carbon atoms. This group may be converted to a--CONH₂ group at any convenient stage in the synthesis of the compoundsof formula II, by reaction with ammonia or an ammonia yielding compound.

The compounds in which R² and/or R³ represent benzyl groups may beconverted into the compounds in which R² and/or R³ represent hydrogenatoms by catalytic hydrogenolysis.

The compounds in which R² and R³ represent hydrogen atoms may beconverted into the compounds in which R² is the radical R¹ bycondensation with an appropriate aldehyde or ketone, followed byreduction of the azomethine so formed, with for example a complex metalhydride or hydrogen and a noble metal catalyst. For example, when thecarbonyl compound used in this reaction is 4-phenyl-2-butanone, CH₃COCH₂ CH₂ Ph, the resulting R¹ radical is --CH(Me)CH₂ CH₂ Ph.

Alternatively, the compounds in which both R² and R³ represent benzylgroups may be subjected to reductive alkylation with an appropriatecarbonyl compound, to give the compounds in which R² is R¹, and R³ ishydrogen, in one step.

It will of course be understood that the reactions used for convertingthe group --COOR⁴ to a --CONH₂, for reducing the carbonyl group to theCHOH group, and for converting the group --CH₂ NR² R³ to --CH₂ NHR¹ maybe carried out in any desired order at any convenient stage in thesynthesis of the compounds of formula II.

In an alternative process for the production of the compounds accordingto the invention, a glyoxal of formula VII, in which X has the meaninggiven below, is used as the starting material. On reaction with an amineof formula R¹ NH₂, the glyoxal yields an intermediate azomethine offormula VIII, which is then reduced, with for example, a complex metalhydride e.g. sodium borohydride, or hydrogen and a noble metal catalyst,followed if necessary by conversion of the group X to --CONH₂, to give acompound of formula II ##STR6##

This method is described in application Ser. No. 699,263 referred toabove the disclosure of which is herein incorporated by way ofreference.

The phenolic hydroxy group of the starting materials and intermediatecompounds may if desired be protected, e.g. as a benzyl ether or anacetate, during the synthesis. The protecting group is removed whenrequired by hydrolysis or catalytic hydrogenolysis.

The compounds according to the invention may be formulated for use inhuman or veterinary medicine for therapeutic or prophylactic purposes.The invention therefore includes within its scope pharmaceuticalcompositions comprising as active ingredients compounds of generalformula II or physiologically acceptable addition salts thereof. Asstated preferred salts include the hydrochloride, sulphate, maleate,acetate, fumarate, lactate and citrate. Such compositions may bepresented for use in a conventional manner with the aid of carriers orexcipients and formulatory agents as required, and with or withoutsupplementary medicinal agents. These compositions include, forinstance, solid or liquid preparations for oral use, suppositories andinjections. Oral administration is most convenient in the form oftablets which may be prepared according to conventional methods and maybe coated if desired. Injections may be formulated with the aid ofphysiologically acceptable carriers and agents as solutions,suspensions, or as dry products for reconstitution before use. The dosesof the active ingredient which may be used may vary within a wide range.Suitable doses are generally within the range of 5 mg to 1000 mgpreferably 20 mg to 200 mg.

The following Examples illustrate the invention:

EXAMPLE 15-[1-Hydroxy-2-(1-methyl-3-phenylpropyl)aminoethyl]salicylamidehydrochloride Method 1

a. 5-Bromoacetylsalicylamide (2.6 g),N-benzyl-N-(1-methyl-3-phenylpropyl)amine (4.8 g) and methyl ethylketone (50 ml were heated at reflux for 40 minutes. The solvent wasremoved and the residue was treated with benzene. The secondary aminehydrobromide was filtered off and discarded, and the filtrate wasevaporated to dryness. The residue was treated with an excess ofethanolic hydrogen chloride when5-[N-benzyl-N-(1-methyl-3-phenylpropyl)glycyl]salicylamide hydrochloride(1.15 g) crystallised out, m.p. 139°-141°.

b. 5-[N-benzyl-N-(1-methyl-3-phenylpropyl)glycl]salicylamidehydrochloride (0.75 g), 10% mixture of PdO and PtO on carbon catalyst(0.1 g) and ethanol (20 ml) were shaken at room temperature and pressurewith hydrogen until uptake ceased. The catalyst was filtered off and thefiltrate evaporated to dryness. The residue was crystallised fromethanol to give5-[1-hydroxy-2-(1-methyl-3-phenylpropyl)aminoethyl]salicylamidehydrochloride as a white solid (0.40 g), m.p. 188°.

Method 2

5-(N,N-dibenzylglycyl)salicylamide (2.25 kg), benzylacetone (990 g), 10%mixture of PdO and PtO on carbon (150 g), methanol (10 liters) andglacial acetic acid (378 ml) were stirred at 50° in an atmosphere ofhydrogen until 586 liters of hydrogen had been absorbed. The catalystwas filtered off, and the filtrate was evaporated under reduced pressureto a viscous gum, which was dissolved in ethanol (4 liters). Hydrogenchloride (216 g) in ethanol (2.16 liters) was added, followed by ether(5 liters). The hydrochloride was filtered off and dried.

The crude solid (1.79 kg) was recrystallised from a mixture of ethanol(10 liters.) and ethyl acetate (15 liters) to give5-[1-hydroxy-2-(1-methyl-3-phenylpropyl)aminoethyl]salicylamidehydrochloride as a white solid, (1.33 kg), m.p. 187°-9°.

EXAMPLE 25-[1-Hydroxy-2-(1-methyl-3-phenylpropyl)aminoethyl]salicylamide

a. 5-(2-Amino-1-hydroxyethyl)salicylic acid methyl ester hydrochloride(5 g) in ammonium hydroxide (d. 0.880; 100 ml), was allowed to stand for8 hours at room temperature. Removal of the solvent under reducedpressure left 5-(2-amino-1-hydroxyethyl)salicylamide hydrochloride,which crystallised from methanol-ethyl accetate as white needles (3.5g), m.p. > 360°.

b. The amine hydrochloride from the previous experiment (2.3 g), inmethanol, was neutralised with a solution of sodium hydroxide (0.4 g) inmethanol (10 g). The mixture was concentrated and refluxed for 1 hourwith 4-phenyl-2-butanone (1.5 g) in ethanol (100 ml), cooled and reducedby hydrogen at room temperature and pressure, in the presence of a 10%platinum -- charcoal catalyst (1.0 g).

On completion of the reduction, the catalyst and solvent were removed toleave an oil, which was extracted with ethyl acetate, and filtered toremove inorganic material. Evaporation of the solution gave a residuewhich was triturated with ether to yield5-[1-hydroxy-2-(1-methyl-3-phenylpropyl)aminoethyl]salicylamide as awhite solid, m.p. 136°-139°. Crystallization from ethylacetate-cyclohexanone raised the melting point to 141°-143°.

The compounds shown in Table I were prepared by reacting5-(2-amino-1-hydroxyethyl)salicylamide hydrochloride with theappropriate carbonyl compound, using the general method of Example 2(b).

                                      TABLE I                                     __________________________________________________________________________     ##STR7##                                                                     Example                                         Melting                                                                             Yield                   No.  Name of Compound       R                   Point ° C                                                                    %                       __________________________________________________________________________     3   5-[1-hydroxy-2-(p-methoxy-α-methylphenethyl) aminoethyl]salicyl         amide                                                                                                 ##STR8##           155   73.05                    4   5-[1-hydroxy-2-(2-p-methoxyphenoxy-1-methyl- ethyl)aminoethyl]salicyl         amide                                                                                                 ##STR9##           113   42                       5   5-[1-hydroxy-2-(3-p-methoxyphenyl-1-methyl- propyl)aminoethyl]salicyl         amide                                                                                                 ##STR10##          151   63                       6   5-[1-hydroxy-2-(3-phenylpropyl)aminoethyl] salicylamide                       hydrochloride                                                                                         ##STR11##          200   28                       7   5-[1-hydroxy-2-(2-o-methoxyphenoxy-1-methyl- ethyl)aminoethyl]salicyl         amide                                                                                                 ##STR12##          127   53                       8   5-[1-hydroxy-2-(3-p-hydroxyphenyl-1-methyl- propyl)aminoethyl]salicyl         amide hydrochloride                                                                                   ##STR13##          170   47                       9   5-[1-hydroxy-2-(1-methyl-4-phenylbutyl)- amino]ethylsalicylamide                                      ##STR14##          151   42                      10   5-[2-(1-methyl-3,3-diphenylpropyl)-amino- 1-hydroxyethyl]salicylamide          hydrochloride                                                                                        ##STR15##          177   50                      11   5-[1-hydroxy-2-(1-methyl-3-p-tolyl-propyl) aminoethyl]salicylamide            hydrochloride                                                                                         ##STR16##          220 (as hydro- chloride)                                                      233   20                      12   5-{1-hydroxy-2-[3-(3,4-dimethoxyphenyl)-1- methylpropyl]aminoethyl}sa         licylamide hydrochloride                                                                              ##STR17##          115-118                                                                             40                      __________________________________________________________________________

EXAMPLE 135-[1-Hydroxy-2-(1,1-dimethyl-3-phenylpropyl)aminoethyl]salicylamide

A solution of 5-glyoxyloysalicylic acid methyl ester hydrate (1.58 g)and 1,1-dimethyl-3-phenylpropylamine (1.2 g) in methanol (20 ml) wasreflaxed for 30 minutes and then evaporated. The residue was dissolvedin ethanol (50 ml) and was hydrogenated at room temperature and pressurein the presence of 10% platinum-charcoal (0.5 g). Addition of methanol(50 ml), glacial acetic acid (0.45 ml) and more catalyst facilitated thereduction.

When hydrogenation was complete, catalyst and solvent were removed, andthe residual oil was neutralised with sodium bicarbonate and extractedinto ethyl acetate. The organic layer was shaken with concentratedhydrochloric acid, washed with water, dried over magnesium sulphate andevaporated. The yellow oily residue crystallised from ethylacetate-ether to give5-[1-hydroxy-2(1,1-dimethyl-3-phenyl-propyl)aminoethyl]salicylic acidmethyl ester hydrochloride, m.p. 170° (40% yield).

A solution of the above hydrochloride (0.6 g) in methanol (10 ml) andammonium hydroxide (d. 0.880; 10 ml) was allowed to stand at roomtemperature for 48 hours. On evaporation, a residue was obtained whichwas neutralised with sodium bicarbonate solution and extracted withethyl acetate. When dried and evaporated, the solution gave the amide asa white solid, m.p. 154° (63% yield).

A similar reductive alkylation using 5-glyoxyloyl salicylamide hydrateand 1,1-dimethyl-3-phenylpropylamine yielded the same compound.

EXAMPLE 14 The separation of 5-[1-hydroxy-2-(1-methyl-5-phenylpropyl)aminoethyl]salicylamide hydrochloride into the two racemicmodifications. Isomer 1 and Isomer 2

a. Isomer 1

5-[1-Hydroxy-2-(1-methyl-3-phenylpropyl)aminoethyl]salicylamide (3.3g)from Example 2(b) above and benzoic acid (1.2 g) were mixed anddissolved in hot ethanol (7 ml). Ether (20 ml) was added and thesolution was filtered. A further quantity of ether (80) was then added,and the solution was allowed to stand at 0° for 17 hours. The fine whitesolid was filtered off and dried at 25° in vacuo to give the benzoate(2.0 g), m.p. 83°-85°. The filtrate was reserved for the preparation ofIsomer 2.

The benzoate was dissolved in ethanol (4 ml), ether (50 ml) was added,and the solution was allowed to stand at 0° for 17 hours. The solid wasfiltered off and dried at 25° in vacuo to give the benzoate of Isomer 1(1.5 g) m.p. 90°-92°.

A solution of the above compound in ethanol was treated with a slightexcess of ethanolic hydrogen chloride to give the hydrochloride ofIsomer 1, (1 g), m.p. 220°.

b. Isomer 2

The filtrate from the preparation of the crude benzoate of Isomer 1 wasevaporated, and the residue was crysallised from ethyl acetate to give awhite crystalline solid (2.0 g), m.p. 135.6°. Recrystallisation fromethyl acetate gave the benzoate of Isomer 2, (1.5 g) m.p. 141°-142°.

A solution of the above compound in ethanol was treated with a slightexcess of ethanolic hydrogen chloride, followed by an equal volume ofether, to give the hydrochloride of Isomer 2, (1.0 g), m.p. 174°.

The following Examples are of pharmaceutical compositions according tothe invention. The references to active ingredient in these Examplesmeans a compound according to the invention and in particular one of thespecific compounds the preparation of which is described in theforegoing Examples.

EXAMPLE 15 Capsules To prepare 10,000 capsules each containing 20 mg.active ingredient

Mix together 200 g. powdered active ingredient with a sufficientquantity of microcrystalline cellulose B.P.C. and fill into No. 3 hardgelatin capsules so that each capsule contains about 120 mg. of themixture.

Capsules may similarly be prepared each containing 50 mg. of activeingredient.

EXAMPLE 16 Tablets To prepare 5,000 tablets each containing 100 mg.active ingredient

Mix together 500 g. active ingredient, 490 g. microcrystalline celluloseB.P.C., 5 g. magnesium stearate and 5 g. stearic acid B.P. Compress thepowders on a suitable tableting press to produce tablets each 1/4 inchin diameter and weighing about 200 mg.

To prepare 5,000 tablets each containing 200 mg. active ingredient

Mix together 1,000 g. active ingredient, 500 g. lactose and 175 g. maizestarch and sufficient of a 2% aqueous solution of sodium hydroxyethylcellulose to produce a damp cohesive mass. Pass the damp mass through aNo. 14 mesh B.S.S. sieve and dry in a fluidised bed dryer at 60° C. Passthe dried granules through a No. 22 B.S.S. sieve and mix with 60 g.dried maize starch and 15 g. magnesium stearate. Compress the lubricatedgranules on suitable tableting press using 3/8 inch deep concave punchesto produce tablets each weighing about 350 mg.

These tablets may be film coated with suitable film forming materialssuch as methyl cellulose, hydroxypropylmethyl cellulose or ethylcellulose or mixtures of these materials using standard techniques.

The tablets may also be sugar coated by the standard sugar coatingtechniques.

EXAMPLE 17 Injection To prepare an injection containing 10 mg. activeingredient per ml.

Dissolve 10 g. active ingredient and 7.5 g. sodium chloride in 950 ml.water for injection. When solution is complete make up to 1 liter withmore water for injection. Subdivide the solution into suitable sizeampoules (1 ml., 5 ml., or 10 ml.) seal and sterilize by heating in anautoclave.

What is claimed is:
 1. A pharmaceutical composition for the treatment ofhypertension, comprising as active ingredient, an effective amount of5-[1-hydroxy-2-(1-methyl-3-phenylpropyl)aminoethyl]salicylamide or aphysiologically acceptable acid addition salt thereof in associationwith a non-toxic pharmaceutically acceptable carrier.
 2. A compositionas claimed in claim 1 in which said active ingredient is5-[1-hydroxy-2-(1-methyl-3-phenylpropyl) aminoethyl] salicylamide.
 3. Acomposition as claimed in claim 1 in which said active ingredient is5-[1-hydroxy-2-(1-methyl-3-phenylpropyl) aminoethyl) salicylamidehydrochloride.
 4. A composition as claimed in claim 1 in dosage unitform containing from 5 mg to 1000 mg of said active ingredient.
 5. Acomposition as claimed in claim 4 containing from 20 mg to 200 mg ofsaid active ingredient.
 6. A composition as claimed in claim 5 in theform of a tablet.
 7. A method of treating a human patient suffering fromhypertension by blocking both α- and β-adrenergic receptors in thepatient, characterized in that there is administered orally, bysuppository or by injection, an effective amount of a compound havingboth α- and β-blocking activity, which compound is5-[1-hydroxy-2-(1-methyl-3-phenylpropyl)aminoethyl] salicylamide or aphysiologically acceptable acid addition salt thereof.
 8. A method asclaimed in claim 7 in which said compound is administered orally.
 9. Amethod as claimed in claim 8 in which said compound is administered intablet form.
 10. A method as claimed in claim 9 in which each tabletcontains from 20 mg to 200 mg of said compound.